An omega-3 fatty acid is also referred to as an omega-3 unsaturated fatty acid, an omega-3 highly unsaturated fatty acid, or a polyunsaturated fatty acid (PUFA). Typical examples thereof are docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), arachidonic acid (ARA), docosapentaenoic acid, α-linolenic acid, and combinations thereof. An omega-3 fatty acid may be used in an alkyl ester form thereof, for example, DHA or EPA, for example, as an ethyl ester of DHA or EPA. Pharmaceutical products including about 90% or more of omega-3 fatty acid ethyl ester (usually referred to as “omega-3-acid ethyl esters 90”) as an active ingredient are current commercially available under the product name “Omacor™” or “LOVAZA™” in the market, including Korea, Europe, and U.S.A. An omega-3 fatty acid or an alkyl ester thereof is used for the treatment of patients with a mixed type of hypercholesterolemia and hypertriglyceridemia (type IIb) at uncontrollable triglyceride levels.
A statin-based drug is a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and used to lower blood cholesterol levels. Examples of statin-based drugs include simvastatin, atorvastatin, rosuvastatin, lovastatin, pitavastatin, cerivastatin, fluvastatin, mevastatin, and pravastatin.
There has been active research into co-administration of an omega-3 fatty acid such as omega-3-acid ethyl ester 90, and a statin-based drug. For example, the co-administration of omega-3-acid ethyl ester 90 and atorvastatin (for example, Lipitor™) is reported to be more efficient to control blood total cholesterol, triglyceride (TG), and very low-density lipoprotein (VLDL) levels, compared to the administration of atorvastatin alone (Bays, H. E. B., et al., Effects of prescription omega-3-acid esters on non-high-density lipoprotein cholesterol when administered with escalated doses of atorvastatin. Mayo. Clin. Proc., 85, 122-128 (2010)). Co-administration of omega-3-acid ethyl ester 90 and atorvastatin is reported to have a synergistic effect on improving TG, high-density lipoprotein (HDL), and cholesterol levels, compared to the administration of omega-3-acid ethyl ester 90 or atorvastatin alone (Chan, D. C., et al., Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. Eur. J. Clin., Invest., 32, 429-436, 2002). Reportedly, the co-administration of omega-3-acid ethyl ester 90 and rosuvastatin results in an improved liquid profile compared to the monotherapy, and also could be used as an alternative therapy for patients with mixed hyperlipidemia (Lee, S. U., et al., Comparison of rosuvastatin plus omega-3 fatty acids combination therapy and rosuvastatin monotherapy in the treatment of mixed hyperlipidemia: An 8-week randomized trial. Atherosclerosis supplement, 2009, Vol. 10, p. 489). Reportedly, the co-administration of Omacor™ and a statin-based drug may improve a lipid profile in patients with persistent hypertriglyceridemia, compared to the monotherapy, which is attributed to the LDL and VLDL improvement effects of a statin-based drug and reduced secretion of VLDL in the liver due to omega-3-acid ethyl ester 90 (Bays, H., et al., Prescription omega-3 fatty acids and their lipid effects: physiological mechanisms of action and clinical implications, Expert Review of Cardiovascular Therapy, 2008, 6(3), 391-409; and Maki, K. C., et al., Omega-3 fatty acids for the treatment of elevated triglycerides Clin Lipidology, 2009, 4(4). 425-437). In addition, it was reported that the co-administration of EPA as an ingredient of omega-3-acid ethyl ester 90 with a statin-based drug may significantly improve total serum cholesterol and TG levels and increase HDL levels in patients with cardiovascular disease, and thus may be an efficient therapy to treat hyperlipidemia (Farooqui, A., et al., Comparison of biochemical effects of statin and fish oil in the brain: The battle of titans. Brain Research Reviews, 2007, 56, 443-471).
There have been attempts to develop composite formulations including an omega-3 fatty acid, such as omega-3-acid ethyl ester 90, and a statin-based drug. For example, Korea Patent Publication No. 10-2007-0038553 discloses a pharmaceutical composition including an omega-3 fatty acid and a statin-based drug (pravastatin). According to the disclosure, the stability of this formulation is highly dependent on types of salts, and about 3% of lactone and about 2% to about 3% of other degradation products may be generated. Korea Patent Publication No. 10-2007-0083715 discloses a suspension including a microcapsule consisting of a statin-based drug (for example, simvastatin) and a polymer in order to ensure the stability of the statin-based drug. Korea Patent Publication No. 10-2007-0108945 discloses a pharmaceutical composition in a homogeneous solution form that includes a statin-based drug in a solvent system including omega-3 fatty acid, but with about less than 10% of the statin-based drug remaining undissolved in the solvent system, due to the failure of complete dissolution of the statin-based drug in the solvent system.